Abnormal Cystic Fibrosis Research Articles

Improvement in cystic fibrosis newborn screening program outcomes with genetic counseling via telemedicine.

The Cystic Fibrosis Foundation (CF Foundation) recommends the provision of genetic counseling (GC) to help educate families and decrease anxiety around the cystic fibrosis (CF) newborn screening process. Unfortunately, access to genetic counselors is limited, especially for CFtrained genetic counselors. We hypothesized that the GC process for families could be improved by utilizing telemedicine to leverage the availability of two dedicated, CF trained genetic counselors to provide access to GC for several CF centers. In addition, we hoped to demonstrate that use of trained CF genetic counselors, delivering GC via telemedicine at the time of sweat testing, would provide families with understanding of CF genetics as well as result in high satisfaction with the newborn screening process. GC was provided by CF trained genetic counselors via telemedicine at the time of sweat testing. Following the counseling session, families were administered an anonymous written survey to evaluate their impression of the services provided. A subset of 50 families was recruited for an assessment of gained knowledge regarding CF genetics using the Ciske knowledge inventory. Using χ2 analysis, Ciske knowledge inventory data from our telemedicine GC families was compared to counseled and uncounseled Ciske historical controls. Lastly, in-depth interviews about the newborn screening process for CF were performed with 10families and interviews were coded for emerging themes. During the 4years of the study, 250 patients received GC. Overall comfort with the counseling rated 4.77 out of 5 using a Likert scale. After counseling by telemedicine, parents demonstrated improved understanding of the genetic implications of an abnormal CF newborn screen for their family, with 100% of families understanding that their child was a carrier for CF as compared to 97.2% of counseled (p = .023) and 78.5% of uncounseled (p = .0007) from Ciske historical controls. The study group also showed improvement in understanding of both parents possibly being carriers, with an 87.7% correct response rate compared to a 37.0% correct response rate in the counseled group (p < .0001) and a 35.4% correct response rate in the non-counseled group (p < .0001) from Ciske historical controls. Subgroup analysis at one site showed a significant increase in the number of infants with completed sweat tests from previous years (49% in 2013 vs. 80% in 2017 during the study, p < .0001). GC by telemedicine was well received by families and demonstrated improved family knowledge acquisition and understanding of CF as it related to risks for their child as well as identification of risks for other family members. Furthermore, in addition to an increase is those receiving GC, a subgroup analysis demonstrated a significant increase in the number of infants receiving sweat tests. This study demonstrates that GC via telemedicine for CF is feasible and demonstrates improvement in parent understanding of CF genetics. Furthermore, this method can be implemented effectively across a wide geographical area with a limited number of CF trained genetic counselors to improve access to care for patients and families.

The natural history of cystic fibrosis liver disease a prospective cohort study

BackgroundOur understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. Aimto determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). MethodsThe Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) Results480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99–10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD.During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59–12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44–3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77–1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. ConclusionThe incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children.

EPS5.01 Change in gut microbiota following elexacaftor/tezacaftor/ivacaftor (ETI) therapy: preliminary analysis

Objectives: Abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with gut dysbiosis in people with cystic fibrosis. The recently introduced elexacaftor/tezacaftor/ivacaftor (ETI) therapy has proved highly effective at improving clinical status, reducing pulmonary exacerbations and increasing weight. There is presently little data on the impact of ETI on CF-related gut dysbiosis. In this study, we explored compositional changes of the gut microbiota following ETI therapy.

Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the "First in Cystic Fibrosis" Phase I Clinical Trial (CEASE-CF).

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the "First in CF" Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.

α-Tocopherol Pharmacokinetics in Adults with Cystic Fibrosis: Benefits of Supplemental Vitamin C Administration.

Background: Numerous abnormalities in cystic fibrosis (CF) could influence tocopherol absorption, transportation, storage, metabolism and excretion. We hypothesized that the oxidative distress due to inflammation in CF increases vitamin E utilization, which could be positively influenced by supplemental vitamin C administration. Methods: Immediately before and after receiving vitamin C (500 mg) twice daily for 3.5 weeks, adult CF patients (n = 6) with moderately advanced respiratory tract (RT) disease consumed a standardized breakfast with 30% fat and a capsule containing 50 mg each hexadeuterium (d6)-α- and dideuterium (d2)-γ-tocopheryl acetates. Blood samples were taken frequently up to 72 h; plasma tocopherol pharmacokinetics were determined. During both trials, d6-α- and d2-γ-tocopherols were similarly absorbed and reached similar maximal plasma concentrations ~18–20 h. As predicted, during vitamin C supplementation, the rates of plasma d6-α-tocopherol decline were significantly slower. Conclusions: The vitamin C-induced decrease in the plasma disappearance rate of α-tocopherol suggests that vitamin C recycled α-tocopherol, thereby augmenting its concentrations. We conclude that some attention should be paid to plasma ascorbic acid concentrations in CF patients, particularly to those individuals with more advanced RT inflammatory disease and including those with severe exacerbations.

Diagnostic agreement among experts assessing adults presenting with possible cystic fibrosis: need for improvement and implications for patient care.

Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies. We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α). Agreement over diagnosis (α=0.282), ease of classification (α= -0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5-10 years versus <5 years) and location (UK and Ireland versus Canada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that "Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators". Our results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement.

New Concepts in the Pathogenesis of Cystic Fibrosis-Related Diabetes.

Cystic fibrosis-related diabetes (CFRD) is the most common extrapulmonary complication of cystic fibrosis (CF). Approximately 40% of people with CF who are older than 20 years have CFRD. Presence of CFRD is associated with poor health outcomes in people with CF. This review summarizes current knowledge on pathophysiology of CFRD. A PubMed review of the literature was conducted, with search terms that included CFRD, cystic fibrosis, cystic fibrosis related diabetes, and cystic fibrosis transmembrane conductance regulator (CFTR). Additional sources were identified through manual searches of reference lists. Pathophysiology of CFRD: The pathophysiology underlying development of glucose tolerance abnormalities in CF is complex and not fully understood. β-cell loss and functional impairment of the remaining β-cell function results in progressive insulin insufficiency. Factors that may contribute to development of CFRD include local islet and systemic inflammation, alterations in the incretion hormone axis, varying degrees of insulin resistance and genetic factors related to type 2 diabetes. The prevalence of CFRD is expected to further increase with improving life expectancy of people with CF. Further research is needed to better understand the mechanisms underlying the development of CFRD and the impact of diabetes on clinical outcomes in CF.

Newborn Screening for Cystic Fibrosis: Infant and Laboratory Factors Affecting Successful Sweat Test Completion

Newborn screening (NBS) for Cystic Fibrosis (CF) has revolutionized the diagnosis of this inherited disease. CF NBS goals are to identify, diagnose, and initiate early CF treatment to attain better health outcomes. Abnormal CF NBS infants require diagnostic analysis via sweat chloride testing (ST). During ST, insufficient sweat volume collection causes a “quantity not sufficient” (QNS) test result and may delay CF diagnosis. The CF Foundation recommends QNS rates <10% for infants <3 months, but many CF Centers experience difficulties meeting this standard. Our quality improvement (QI) study assessed infant and laboratory factors contributing to ST success and QNS rates from 2017–2019. Infants’ day of life (DOL) at successful ST completion was analyzed according to infant factors (birth weight (BW), gestational age, ethnicity, and sex). Laboratory factors and procedures affecting ST outcomes were also reviewed. At our institution, BW and gestational age were the infant factors found to significantly affect DOL at ST completion. ST education, reduced number of laboratory technicians, and direct observation during ST completion also improved ST success rates. This study supports QI measures and partnerships between CF centers and laboratory staff to identify and improve ST QNS rates while sustaining practices to ensure timely CF diagnostic testing.

Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus

In response to respiratory insults, airway submucosal glands secrete copious mucus strands to increase mucociliary clearance and protect the lung. However, in cystic fibrosis, stimulating submucosal glands has the opposite effect, disrupting mucociliary transport. In cystic fibrosis (CF) pigs, loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channels produced submucosal gland mucus that was abnormally acidic with an increased protein concentration. To test whether these variables alter mucus, we produced a microfluidic model of submucosal glands using mucus vesicles from banana slugs. Acidic pH and increased protein concentration decreased mucus gel volume and increased mucus strand elasticity and tensile strength. However, once mucus strands were formed, changing pH or protein concentration largely failed to alter the biophysical properties. Likewise, raising pH or apical perfusion did not improve clearance of mucus strands from CF airways. These findings reveal mechanisms responsible for impaired mucociliary transport in CF and have important implications for potential treatments.

Unveiling epidemiology and treatment strategies for efficient management of lung infection in cystic fibrosis

Cystic Fibrosis (CF) is a genetic disorder which results in abnormal Cystic Fibrosis Transmembrane Regulator (CFTR) protein. CFTR protein actively transports chloride and bicarbonate out of cells which produce mucus in epithelium of various organs. However, when there is an abnormality in this protein then ion and water transport across airway surface is affected and form viscous mucus due to dehydration. This disease affects lung, pancreases, intestine and hepatobiliary system. Infection of lungs is main reason of high morbidity and mortality. Patients with CF are more prone to bacterial infection of the respiratory tract. Mainly four bacterial pathogens are found in the respiratory tract of CF patient viz. Staphylococcus aureus, Haemophilus influenzae, Burkholderia cepacia, Pseudomonas aeruginosa. Mucoid P. aeruginosa is the most dangerous pathogen among them due to ability to form biofilm. There are many conventional and new treatment options available for CF patients. New therapies are used to correct the CFTR protein and antibiotic treatment is used to prevent or early infection or suppression of chronic infection. However, when P. aeruginosa turn into mucoid form, formation of extracellular polysaccharide biofilm starts with alginate as major constituent. The antibiotics fail to reach the target as EPS of the biofilm shield the microbe from antibiotics action. Alginate lyase, an alginate degrading has the ability to break the alginate and subsequently increases the efficacy of antibiotics therapy. The co-administration of alginate lyase and Dnase along with antibiotics has proved to be very efficient in the management of patients with CF.

Cystic fibrosis related diabetes: Medical management

Cystic Fibrosis Related Diabetes Mellitus (CFRD) drives excess pulmonary morbidity and mortality in patients with cystic fibrosis (CF). The recommended treatment is insulin therapy. Insulin therapy in CF should be customized to the specific patient. CF patients typically require intensive insulin regimens such as multiple daily injections or insulin pump therapy, but frequently require lower doses than in type 1 diabetes mellitus. Patients with CF may also need insulin to cover intravenous or enteral feedings. Pre-diabetic glycaemic abnormalities are also associated with clinical decline in cystic fibrosis prior to the diagnosis of CFRD, however, whether and how this should be treated is not fully determined. There is also interest, but inadequate data regarding other treatments besides insulin (i.e., oral medications) for treatment of pre-diabetes or CFRD. CFTR potentiator and corrector therapy has yet to demonstrate an effect on the rate of CFRD, but may improve insulin secretion. There is great opportunity for further research to better understand when and how best to treat glycaemic abnormalities in cystic fibrosis.

1500-P: Continuous Glucose Monitoring and Beta-Cell Function in Youth with Cystic Fibrosis

Continuous glucose monitoring (CGM) is frequently used to assess glucose abnormalities in cystic fibrosis (CF) prior to frank diabetes, yet the biological significance of various CGM measures is unclear. Our aim is to identify CGM measures correlated with β-cell function decline in youth with CF. CGM and 2 hour oral glucose tolerance testing (OGTT) were collected in youth with CF and healthy controls (HC). Glucose and insulin were measured at baseline and 30 minutes on OGTT. Insulinogenic index [IGI=(insulin30-insulin0)/(Glucose30-Glucose0)] was used to estimate β-cell function. Eighty-one participants were included in the analysis [15 HC, 13 CF normal glucose tolerance (NGT), 41 CF abnormal glucose tolerance, and 12 CF related diabetes by OGTT]. There were no differences in age (13.6±3.5 years), sex, race, nor BMI z-score among groups. IGI was significantly lower in all CF groups, even CF NGT, compared to HC (p&amp;lt;0.0001). Table 1 presents correlations between CGM measures and IGI. Youth with CF, despite NGT by OGTT, have impairments in insulin secretion. Greater peak glucose, %time &amp;gt;140 mg/dl, and glucose variability (SD and MAGE), but not measures of average nor low glucose, on CGM correlate with declines in β-cell function. Further studies are needed to determine whether these CGM measures predict clinical decline in CF. Disclosure C.L. Chan: None. T.B. Vigers: None. L. Pyle: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc. K.J. Nadeau: None. Funding Cystic Fibrosis Foundation (CHAN16A0, CHAN16GE0); National Institutes of Health (DK094712-04)

P294 Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review

P294 Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review

Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis

Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways.

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.

Quantitative multivolume proton-magnetic resonance imaging in patients with cystic fibrosis lung disease: comparison with clinical indicators.

This cross-sectional study aims to verify the relationship between quantitative multivolume proton-magnetic resonance imaging (1H-MRI) and clinical indicators of ventilatory abnormalities in cystic fibrosis (CF) lung disease.Non-enhanced chest MRI, spirometry and multiple breath washout was performed by 28 patients (10-27 years) with CF lung disease. Images acquired at end-inspiration and end-expiration were registered by optical flow to estimate expiratory-inspiratory proton-density change (Δ1H-MRI) as a measure of regional ventilation. Magnetic resonance images were also evaluated using a CF-specific scoring system.Biomarkers of CF ventilation impairment were defined from the Δ1H-MRI as follows: Δ1H-MRI median, Δ1H-MRI quartile coefficient of variation (QCV) and percentage of low-ventilation volume (%LVV). Imaging biomarkers correlated to all the clinical measures of ventilation abnormality, with the strongest correlation between Δ1H-MRI median and forced expiratory volume in 1 s (r2=0.44, p<0.001), Δ1H-MRI QCV and lung clearance index (LCI) (r2=0.51, p<0.001) and %LVV and LCI (r2=0.66, p<0.001). Correlations were also found between imaging biomarkers of ventilation and morphological scoring.The study showed a significant correlation between quantitative multivolume MRI and clinical indicators of CF lung disease. MRI, as a non-ionising imaging technique, may be particularly attractive in CF care for longitudinal evaluation, providing a new imaging biomarker to detect early ventilatory abnormalities.

Regional analysis of airway abnormalities in cystic fibrosis employing Electrical Impedance Tomography

Abstract To estimate the severity of airway abnormalities in cystic fibrosis (CF) Brody et al. developed a computed tomography (CT) scoring system. Each pulmonary lobe is analyzed separately considering various morphological defects. A study from Zhao et al. demonstrates that this CTbased score correlates with regional airway obstruction (RAO) measured by the real-time imaging method Electrical Impedance Tomography (EIT). Zhao et al. performed EIT measurements at the 5th intercostal space (ICS) and median RAO, including both lungs, was correlated with the associated score. In the present feasibility study, it was investigated if RAO determined by EIT within the left and right lung respectively at the 3rd and 5th ICS corresponds with the scores of the left and right lobes. EIT measurements and CT-based scoring were carried out on two CF patients. RAO was identified by ratios of impedance values associated to the maximal forced expiratory flow at 25% and 75% of the forced vital capacity. Mean RAO of each lung within both thorax sections was compared with the lobar scores. Airway abnormalities within upper lobes are assigned to RAO measured within the 3rd ICS, whereas abnormalities of the right middle lobe, both lower lobes and the lingula are mainly represented by EIT images of the 5th ICS. Results show that differences in the CT-based score between the left and right lung concur with differences in EIT derived RAO. The regional information provided by EIT might be used for a more targeted therapy of CF-related lung diseases.

Dietary interventions for managing glucose abnormalities in cystic fibrosis: a systematic review protocol

BackgroundGlucose abnormalities in cystic fibrosis (CF) are common, but there is limited evidence to guide their dietary management. Progressive impaired glucose tolerance eventually leads to cystic fibrosis-related diabetes (CFRD), the most prevalent complication of CF, which is associated with increased morbidity and mortality. Optimising glycaemic control improves clinical status and reduces mortality; insulin therapy is the primary means of controlling glycaemia in CFRD, but its role in managing pre-diabetes is less clear. CF dietary therapy requires a high calorie diet due to increased energy expenditure and malabsorption, but this energy-dense diet is typically high in fat and sugar, and high sugar intakes often result in hyperglycaemia in individuals who have impaired glucose handling. Current guidelines for the dietary management of glucose abnormalities in CF are based on clinical consensus rather than empirical evidence. A systematic review conducted in 2012 on the effects of low glycaemic index dietary intervention in CF concluded that there is a dearth of evidence in this area. This review will update the systematic review by Balzer et al. in 2012 and will broaden the scope of their review to include any type of dietary intervention for managing glucose abnormalities in CF.MethodsQuantitative studies of dietary interventions to manage glucose abnormalities in individuals aged over 5 years with CF and glucose abnormalities will be reviewed. No limits will be placed on language or study design. The comparator will be standard CF dietary therapy (energy dense, high-fat diet) in addition to insulin therapy for individuals with CFRD. Electronic databases will be searched for completed quantitative studies published in peer-review journals that focus on dietary interventions for managing glucose abnormalities in CF. Searches will be conducted from 2000 up to the present day to reflect the evolving improvements in CF management. No restrictions will be placed on study design or language. Duration of the dietary intervention must be a minimum of 2 months and only interventions in out-patient or community settings will be included. Studies must report on dietary intervention, glycaemic control, anthropometry and lung function. Evidence will be assessed for heterogeneity and a narrative review or meta-analysis conducted as appropriate.DiscussionThis systematic review will elucidate current knowledge of the effects of dietary interventions for managing glucose abnormalities in the vulnerable CF clinical population.Systematic review registrationPROSPERO registration number: CRD42018085569www.crd.york.ac.uk/prospero/

Continuous glucose monitoring to evaluate glycaemic abnormalities in cystic fibrosis

ObjectiveThis study aimed to determine the glycaemic profile of patients with cystic fibrosis using a continuous glucose monitoring system (CGMS), and to evaluate the associations of glycaemic abnormalities with sex,...

Toward inclusive therapy with CFTR modulators: Progress and challenges.

Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre-clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cell-based tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation.